Adults and children with severe hemophilia A who are receiving Nuwiq (recombinant human coagulation factor VIII) as their first replacement therapy have a similar risk of developing inhibitors as those treated with plasma-derived therapies containing von Willebrand factor, the final results of the NuProtect trial show.
Nuwiq also was found to be effective in preventing and treating bleedings in these patients, who had not been treated previously for hemophilia.
The findings were presented at the 62nd American Society of Hematology (ASH) Annual Meeting & Exposition, held recently in San Diego. The presentation was given by Ri Liesner, MD, director of the Hemophilia Comprehensive Care Centre at the Great Ormond Street Hospital for Children, in the U.K.
Liesner spoke on a communication titled “Inhibitor Development with Simoctocog Alfa in Previously Untreated Patients with Severe Haemophilia a: Final Results of the Nuprotect Study.”
One of the major hurdles of replacement therapy — one of the standard treatments for hemophilia A — is the formation of inhibitors that can severely block the therapy’s effectiveness in some patients. Replacement therapy involves supplying the blood-clotting factor that is missing in those with the disease. In this case, that’s factor VIII (FVIII), also called antihemophilic factor.
Inhibitors are antibodies that develop when the immune system mistakenly views the replacement clotting factor as foreign or harmful. That triggers the immune system to then produce antibodies that target these factors for destruction.
Scientists say the development of anti-FVIII inhibitors is, in fact, the greatest challenge faced in treating hemophilia A patients for the first time.
That problem occurred among toddlers with severe hemophilia A receiving their first-ever treatment in the SIPPET study (NCT01064284). The results showed that 44.5% of the children treated with recombinant FVIII (rFVIII) — made in the lab using hamster cells — and 26.8% of those treated with plasma-derived FVIII containing von Willebrand factor (pdFVIII/VWF) ended up developing inhibitors during the course of the trial. Plasma-derived FVIII containing von Willebrand factor (pdFVIII/VWF) is sold under the brand names Alphanate, Humate-P, and Koate-DVI.
Nuwiq (simoctocog alfa; human recombinant FVIII) is a replacement therapy by Octapharma indicated for the prevention (prophylaxis) and treatment of bleeding episodes in adults and children with hemophilia A. It is made of a human rFVIII produced in a human cell line in the lab, without any chemical modification or joining of other proteins. The therapy is delivered directly by infusions into the bloodstream (intravenous injections).
Octapharma conducted the NuProtect Phase 3 trial (NCT01992549) to determine the long-term immunogenicity — how frequently treated patients developed inhibitors — as well as the efficacy and safety of Nuwiq in untreated adults and children with severe hemophilia A.
A preliminary analysis of the results, reporting data from 66 patients of all ages who were exposed to Nuwiq for more than 20 days, showed that 20.8% developed inhibitors. Among those patients, 12.8% developed a high concentration of inhibitors, referred to as a high-titre.
At ASH 2019, Liesner presented the final results of the trial, including data on 105 previously untreated patients, median age 12 months, who were exposed to Nuwiq a median of 101 days. Most participants were treated for 100 or more days or until inhibitor development.
Among the participants, 13 (12.0%) had a family history of inhibitors and most had null F8 gene mutations (88.2%). Null mutations, those that completely prevent the formation of a working clotting factor, are considered high-risk mutations, while non-null mutations are considered low-risk. People with high-risk mutations in the gene F8, which codes for FVIII, have a higher risk of developing inhibitors.
During the entire course of the study, 27.9% of the patients developed inhibitors, of whom 17.6% developed a high-titre (5 or higher Bethesda unit/mL) of inhibitors.
In terms of efficacy, constant prophylactic treatment with Nuwiq for six months or more in 50 patients yielded a mean annualized bleeding rate of 0.54 for spontaneous bleedings and 3.61 for all types of bleedings.
Nuwiq also was successful in treating 92.9% of the bleeding episodes occurring over the trial (747 events out of 804, in 85 patients), with 91.9% of these events being controlled with one or two infusions.
In addition, using Nuwiq to manage bleeding during surgery was fully effective in 18 of 19 interventions (94.7%), and moderately so in one of them.
None of the patients who carried non-null F8 mutations (low-risk) developed inhibitors. Apart from the development of inhibitors, only one patient had a serious side-effect, a hospitalization due to a mild rash that resolved with treatment.
Overall, the results show that Nuwiq had a similar inhibitor incidence as plasma-derived products containing von Willebrand factor.
“These results complement results in previously treated patients (PTPs) and support the use of simoctocog alfa [Nuwiq] in the prevention and treatment of BEs [bleeding episodes]” in previously untreated patients and previously treated patients, the researchers said.
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